The_Safety_Pharmacokinetics_and_Effects_of

The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men
dose muscle baseline group placebo LGD
The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men
dose muscle baseline group placebo LGD
See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/223988321
The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel
Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy
Young Men
Article  in  The Journals of Gerontology Series A Biological Sciences and Medical Sciences  March 2012
DOI: 10.1093/gerona/gls078  Source: PubMed
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1
 AS men and women grow old, they lose muscle mass, 
muscle strength , and leg power ( 1 , 2 , 3 , 4 , 5 , 6 ), mostly 
due to the preferential loss of type  II  muscle fi bers ( 5 ). 
Sarcopenia, the age-associated loss of muscle mass and 
strength, increases the risk of falls, fractures, physical dis-
ability, and poor quality of life ( 1 , 3 , 6 , 7 ). Similarly, the 
course of many illnesses, such as chronic obstructive lung 
disease, end - stage renal disease, and some types of cancer, 
is punctuated by the loss of muscle mass and physical func-
tion, which contributes to mobility limitation and disability 
( 7 , 8 ). Thus, there is an unmet need for anabolic therapies 
that improve physical function and reduce the burden of 
disability in persons experiencing functional limitations 
due to aging or illness. Among the various candidate function -
 promoting anabolic therapies that are in development, 
androgens are the farthest along in development. 
 Testosterone administration increases muscle mass and 
strength ( 9 , 10 , 11 , 12 , 13 , 14 , 15 ), but concerns regarding its 
potential adverse effects on the prostate have restrained 
enthusiasm for its use as an anabolic therapy and have 
motivated efforts to develop selective androgen receptor 
modulators (SARMs), a new class of androgen receptor 
 The Safety, Pharmacokinetics, and Effects of 
LGD-4033, a Novel Nonsteroidal Oral, Selective 
Androgen Receptor Modulator, in Healthy Young Men 
 Shehzad  Basaria , 1  Lauren  Collins , 1 , *  E. Lichar  Dillon , 2 , *  Katie  Orwoll , 1  Thomas W.  Storer , 1 
 Renee  Miciek , 1  Jagadish  Ulloor , 1  Anqi  Zhang , 1  Richard  Eder , 1  Heather  Zientek , 3  Gilad  Gordon , 3  
 Syed  Kazmi , 3  Melinda  Sheffi eld-Moore , 2 , * and  Shalender  Bhasin 1 
 1 Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Massachusetts .  
 2 Department of Medicine, University of Texas Medical Branch, Galveston .  
 3 Ligand Pharmaceuticals , San Diego, California .  
 * These authors contributed equally and are joint second authors. 
 Address correspondence to Shalender Bhasin, MD, Section of Endocrinology, Boston University School of Medicine, Boston, MA 02118. 
Email:  Bhasin@bu.edu 
 Background.  Concerns about potential adverse effects of testosterone on prostate have motivated the development of 
selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a 
novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affi nity and selectivity. 
 Objectives.  To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 admin-
istered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones. 
 Methods.  In this placebo-controlled study, 76 healthy men (21  50 years) were randomized to placebo or 0.1, 0.3, or 
1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specifi c antigen, electrocardiogram, 
hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention. 
 Results.  LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was 
similar between active and placebo groups. Hemoglobin, prostate-specifi c antigen, aspartate aminotransferase, alanine 
aminotransferase, or QT  intervals did not change signifi cantly at any dose. LGD-4033 had a long elimination half-life and 
dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent 
suppression of total testosterone, sex hormone  binding globulin, high density lipoprotein cholesterol, and triglyceride 
levels. Follicle-stimulating hormone and free testosterone showed signifi cant suppression at 1.0-mg dose only. Lean body 
mass increased dose dependently, but fat mass did not change signifi cantly. Hormone levels and lipids returned to baseline 
after treatment discontinuation. 
 Conclusions.  LGD-4033 was safe, had favorable pharmacokinetic profi le, and increased lean body mass even during 
this short period without change in prostate-specifi c antigen. Longer randomized trials should evaluate its effi cacy 
in improving physical function and health outcomes in select populations. 
 Key Words:  Selective androgen receptor modulators  SARMs  Sarcopenia  Function promoting anabolic therapies 
 Cachexia . 
 Received  December  8 ,  2011 ;  Accepted  February  2 ,  2012 
 Decision Editor: Luigi Ferrucci, MD, PhD 
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88 
BASARIA ET AL.
2
ligands that are tissue  selective ( 8 , 16 , 17 , 18 , 19 ). The last 
decade has witnessed substantial pharmaceutical efforts to 
develop nonsteroidal SARMs to treat muscle wasting and 
functional limitations associated with acute and chronic ill-
ness and aging ( 8 , 16 , 17 , 18 , 19 ). LGD-4033 is a novel non-
steroidal, oral SARM that binds to androgen receptor with 
high affi nity (Ki of  ~ 1  nM) and selectivity. In animal models, 
LGD-4033 has demonstrated anabolic activity in the mus-
cle, anti-resorptive and anabolic activity in bone, and robust 
selectivity for muscle versus prostate. 
 Here we report the results of a randomized, double-blind, 
placebo-controlled, ascending-dose study, which evaluated 
the safety, tolerability, and pharmacokinetics  (PK)  of LGD-
4033 in healthy men. We also evaluated the effects of graded 
doses of LGD-4033 on lean body mass (LBM), muscle 
strength , and physical function. LGD-4033 doses of 0.1, 
0.3, and 1.0 mg were selected for multiple dosing over 21 
 days because a previous phase I single ascending-dose study 
had established the safety of up to 22  mg LGD-4033. We also 
tested the hypothesis that the LGD-4033 increases muscle 
mass by stimulating fractional synthetic rate (FSR) of mixed -
 muscle proteins, measured using continuous steady  state 
infusion of labeled phenylalanine in men randomized to either 
placebo or 0.3-mg daily dose of LGD-4033. This dose was 
selected for FSR study because preclinical data suggested 
that this dose was the most likely to increase LBM. 
 Study Design 
 This was a double-blind, placebo-controlled, multiple 
once-daily dose escalation study of LGD-4033 in healthy 
men, approved by Boston University ' s Institutional Review 
Board. All subjects provided written, informed consent. 
 Subjects 
 Nonsmoking, healthy men, 21  50 years, with body mass 
index between 18 and 32 kg/m 2 , who were capable of 
providing informed consent, were eligible. We excluded 
subjects who had an active disease, prostate-specifi c antigen 
 >3  ng/mL, aspartate aminotransferase or ALT  >1.5 times the 
upper limit of normal, hematocrit  <37% or >48%, creatinine 
 >2.0  mg/dL,  and  (HDL) cholesterol  <40  mg/dL ; had used 
anabolic steroids, recombinant human growth hormone, 
dehydroepiandrosterone , and androstenedione during the 
past year ; or were using any recreational drug. 
 Study Intervention 
 Three dose levels  0.1, 0.3 , and 1.0  mg  were evalu-
ated against placebo. Each dose of LGD-4033 or placebo 
was administered daily orally with 8  ounces of water 
after an overnight fast. A total of 20 doses were adminis-
tered over 21  days; no dose was given on day 2 to allow 
 PK  sampling for 48  hours after the fi rst dose. The 21-day 
treatment period was followed by a 5-week observation 
period. 
 Randomization 
 The subjects were randomized to the active drug or 
placebo group based on protocol-defi ned randomization 
schema:  six  active and  two  placebo in 0.1-mg cohort; 10  12 
active and 10  12 placebo in 0.3-mg and 1.0-mg cohorts. 
A protocol amendment after the completion of 1.0-mg 
cohort added 12 active and  six  placebo subjects in the 
0.1-mg cohort. Randomization lists, generated by the 
biostatistician, were sent directly to Investigational Drug 
Service. 
 The subjects were initially assigned to either placebo or 
0.1  mg LGD-4033 daily. At the completion of each dose 
level, the safety data were reviewed by a Safety Panel and 
separately by a Data and Safety Monitoring Board, which 
determined whether the dose could be escalated to a higher 
level, based on prespecifi ed safety criteria. Dose escalation 
proceeded only if an acceptable safety profi le with no clini-
cally signifi cant and/or unexpected toxicity was observed at 
the lower dose. 
 Blinding 
 The study was a double-blind trial with concealed ran-
domization. The subjects and study personnel were unaware 
of the intervention. Only the biostatistician and  Investi-
gational Drug Service were aware of the subject ' s group 
allocation. The  Investigational Drug Service maintained the 
randomization code and dispensed the study medication 
based on the randomization list. 
 Outcomes 
 The primary aim was to assess the safety and tolerability 
of escalating doses of LGD-4033 following repeated once-
daily oral administration for 21  days. Secondary aims included 
the determination of the PK and pharmacodynamics of 
LGD-4033 and its effects on mixed - muscle FSR. Addition-
ally, we investigated the effects of 21  days of treatment with 
LGD-4033 on LBM measured by dual - energy x-ray absorp-
tiometry, maximal voluntary strength measured by one rep-
etition maximum method, and physical function, assessed 
by the stair-climbing power, recognizing that a 21-day dura-
tion may not be suffi ciently long to fully elucidate the 
anabolic effects of the SARM on LBM, muscle strength, 
and physical function. 
 Schedule of Events 
 LGD-4033 concentrations were measured using a vali-
dated liquid chromatographic  tandem mass spectrometry 
method in venous blood collected at 0, 0.5, 1, 2, 3, 4, 6, 8, 
10, 12, 24, 28, 32, and 48  hours after the fi rst dose. Once-
daily dosing recommenced on day 3 for 20  days , and on day 
 21, venous blood was collected at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 
12, 24, 28, 32, 48, 72, 96, 120 , and 168  hours after day  21 
dosing. 
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THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 
89
3
 Luteinizing hormone, follicle-stimulating hormone, 
adrenocorticotropic hormone, cortisol, total and free testos-
terone, sex  hormone  binding globulin levels, and plasma 
lipids were measured periodically throughout the 21-day 
intervention period and 7 and 35 days after drug cessation. 
LBM and fat mass were measured at baseline and on days 
20 and 28. Leg  press strength and stair-climbing power and 
speed were assessed at baseline and between days 23 and 25. 
 M ethods 
 Body composition was assessed using  dual-energy x-ray 
absorptiometry (Hologic 4500) scanner, calibrated using a 
soft tissue phantom before each scan. To measure the leg 
 press strength ( 15 , 20 , 21 ), subjects underwent whole-body 
warm up, followed by one set of 5  10 repetitions using 
40 %  60% of the estimated maximum. Following appropriate 
rest periods between attempts, subjects lifted progressively 
heavier weights until the subject could not complete the lift. 
The last successfully completed lift was recorded as the  one 
repetition maximum . 
 The 12-step stair-climb test required subjects to ascend a 
staircase with step  rise of 17  cm as fast as possible with time 
recorded by activation of switchmats on the 8th and 12th 
stair ( 15 , 20 , 21 ). The test  retest reliability is 0.85 and coef-
fi cients of variation 2%. After familiarization, two trials 
were given with the best time taken as the stair-climb score. 
Power was calculated from the time elapsed, body weight, 
and vertical distance. 
 Fractional Protein Synthesis Rates 
 On days 1 and 20, at 7  am , an 18-gauge catheter was 
inserted into the forearm vein of each arm, one for blood 
sampling and one for tracer infusion. Baseline blood sam-
ples were drawn for analysis of amino acid enrichments from 
one arm, heated with a heating pad. At 8  am , a primed 
(2.0   mol / kg) constant infusion (0.06   mol / kg / min utes ) of 
 l -[ring- 13 C 6 ] phenylalanine was started and maintained for 
6  hours. Venous blood was obtained at 0, 60, 120, 150, 165, 
180, 195, 210, 240, 300, 330, 345, and 360  min utes during 
the infusion. Two muscle biopsies (100  300  mg) were taken 
at 180 and 360  min utes from vastus lateralis,  ~ 10  to  15  cm 
above the knee, using a 5-mm Bergstrom biopsy needle, and 
snap frozen in liquid nitrogen for storage in a   80  C freezer 
until analysis. 
 Phenylalanine enrichments in arterialized venous blood 
was determined after deproteinization with sulfosalicylic acid, 
extraction with cation exchange chromatography (Dowex AG 
50W-8X, 100  200 mesh H+ form; BioRad Laboratories, 
Richmond, CA), derivatization using  tert -butyldimethylsilyl, 
followed by gas  chromatography  mass  spectrometry in 
electron impact mode (GC HP 5890, MSD HP 5989, Hewlett 
Packard, Palo Alto, CA ;  22 ). 
 Muscle samples were weighed and the proteins precipi-
tated with 800   l of 10% sulfosalicylic acid. Intracellular 
phenylalanine enrichment was determined by extraction 
with cation exchange chromatography (Dowex AG 50W-8X, 
200  400 mesh H+ form; BioRad Laboratories, Inc.),  tert -
butyldimethylsilyl derivatization, and  gas chromatography 
 mass spectrometry in electron impact mode ( 22 ). The 
remaining pellet containing bound mixed-muscle proteins 
was repeatedly washed, dried at 50C overnight , and hydro-
lyzed in 3  mL of 6  N HCL at 110  C for 24  hours. Amino 
acids in the hydrolysate were extracted and derivatized and 
analyzed by monitoring the ions 238 and 240 ( 22 ). 
 Mixed - muscle FSR was calculated by measuring the 
incorporation of  l -[ring- 13 C 6 ]-phenylalanine into protein 
using the precursor  product model:
 
=



P2
P1
M
FSR [(
) /(
)]60 100,
E
E
E
t
 
where  E P1 and  E P2 are enrichments of bound  l -[ring- 13 C 6 ]-
phenylalanine in the fi rst and second muscle biopsies,  t is the 
time between biopsies, and  E M is the mean  l -[ring- 13 C 6 ]-
phenylalanine enrichment in muscle intracellular pool ( 22 ). 
 Hormone Assays 
 Total testosterone was measured using liquid chroma-
tography  tandem mass spectrometry ( 23 ) , and free testos-
terone was calculated using a published law-of-mass-action 
equation ( 24 ). Serum  luteinizing hormone ,  follicle-stimulating 
hormone , and  sex hormone  binding globulin were mea-
sured using two  site - directed immunofl uorometric assays 
( 9 , 21 ). 
 Statistical Analyses 
 Safety parameters were listed and summarized by study 
intervention, dose, and time point. Adverse events were 
tabulated by System Organ Class and Preferred Term based 
on MedDRA dictionary version 12. 
 Plasma drug concentration  time data were analyzed using 
noncompartmental methods.  PK  parameters were summa-
rized by dose group , and selected  PK  parameters were 
analyzed using comparative statistics. Dose proportionality 
of  PK  parameters was assessed by linear regression. 
 Pharmacodynamic assessments were summarized for each 
dose and time point. Changes from baseline in hormone levels, 
lipids, and FSR were analyzed using repeated measures 
analyses of variance, with a dose factor and time-in-treatment 
factor and baseline value as covariate. A similar approach 
was used to analyze change from baseline in LBM,  one rep-
etition maximum strength , and stair-climbing power. 
 For  dual-energy x-ray absorptiometry , muscle strength, 
and stair-climbing power, a trend analysis of change from 
baseline was applied using a mixed-model analysis of re-
peated measures and adjusted for baseline value. Two post-
baseline measures up to day  28 were utilized in repeated 
measure model. This analysis was performed on evaluable 
subjects who had baseline measures and at least one 
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90 
BASARIA ET AL.
4
post-baseline measure. Placebo subjects from the  three  co-
horts were pooled for analysis. This resulted in sample sizes 
of 30 men for  dual-energy x-ray absorptiometry analysis 
and 29 men for muscle strength analysis in the placebo 
group, 17 in the 0.1-mg, 10 in the 0.3-mg, and 11 in the 1.0-mg 
dose groups. 
 R esults 
 Flow of Subjects 
 A total of  389 subjects were screened in person, 131 were 
eligible , and 76 were randomized (CONSORT diagram, 
 Supplementary  Appendix Figure 1 ). Eight subjects were 
either lost to follow-up or discontinued and 68 subjects 
completed the trial. 
 Subjects 
 The participants were young (mean age 37  years), lean 
( body mass index 25.8 kg/m 2 ) , and had normal testosterone, 
 luteinizing hormone , and  follicle-stimulating hormone 
levels ( Table 1 ). The groups were similar in their baseline 
characteristics. 
 Compliance 
 The compliance, assessed by drug  logs and by counting 
the unused tablets, was 100%, among men who were included 
in the effi cacy analysis. 
 Safety Data 
 LGD-4033 was safe and well tolerated at all doses. The 
frequency of adverse events was similar between the pla-
cebo and any dose group. Headache, pain related to muscle 
biopsy, and dry mouth were the most common events and 
did not show dose relationship ( Supplementary  Appendix 
Table 1 ). More upper respiratory tract infections were 
observed in LGD-4033 1.0 - mg group , but these events were 
not considered drug  related. No drug-related severe or serious 
adverse events  occurred. One cellulitis (in placebo group) 
and one gastroenteritis (0.3 mg group) were severe but were 
not considered study drug  related. There was no study dis-
continuation due to adverse events. There were no clinically 
signifi cant  changes in liver enzymes, hematocrit,  prostate-
specifi c antigen , or electrocardiogram at any dose. 
 Pharmacokinetics 
 LGD-4033 displayed a prolonged elimination half-life 
(24  36 hours) and linear  PK  ( Figure 1 ). There was a dose -
 proportional increase in LGD-4033 concentrations on 
days 1 and 21. Serum LGD-4033 concentrations were nearly 
threefold higher on day 21 than on day 1, refl ecting accu-
mulation upon multiple dosing. The mean areas  under  the 
 drug  concentration  curve on day 21 were 19, 85 , and 238 ng 
24 hour/mL, respectively, in men receiving 0.1, 0.3, and 1.0 mg 
LGD-4033 daily. 
 Hormone Levels 
 There was a dose-dependent suppression of total testos-
terone and  sex hormone  binding globulin levels from 
baseline to day 21 ( Figure 2 ). Free testosterone suppres-
sion was noted at the 1.0-mg dose only. The suppression of 
total testosterone was greater than that of free testoster-
one. Serum  luteinizing hormone levels did not show any 
meaningful changes from baseline, whereas the  follicle-
stimulating hormone levels were suppressed only in the 
1.0-mg dose group ( Figure 2D and E ). Upon discontinua-
tion of LGD-4033, the hormone levels returned to baseline 
by day 56. 
 Table 1.  Baseline Characteristics of the Subjects 
 Placebo/LGD Dose Group
Placebo
LGD-4033 Doses
All Subjects 
 0.1 mg
0.3 mg
1 mg 
 N 
33
18
11
14
76 
 Age (years)
36.0 (9.4)
37.0 (10.4)
35.6 (8.4)
40.9 (8.7)
37.1 (9.4) 
 Body weight (kg)
81.5 (13.6)
78.2 (13.9)
80.5 (13.5)
84.6 (10.2)
81.2 (13.0) 
 Height (cm)
176.8 (6.4)
178.0 (9.6)
175.3 (7.3)
176.8 (6.9)
176.9 (7.4) 
 Body mass index (kg/m 2 )
25.9 (3.4)
24.6 (3.0)
26.2 (3.5)
27.0 (2.7)
25.8 (3.3) 
 TESTO  (ng/dL)
549 (136)
564 (153)
543 (111)
551 (144)
552 (136) 
 FT (ng/dL)
11.39 (3.11)
11.4 (3.1)
11.4 (3.4)
11.36 (3.3)
11.2 (3.1) 
 Sex hormone  binding globulin (nmol/L)
34.1 (11.7)
37.5 (21.6)
34.0 (8.6)
36.4 (11.1)
35.3 (14.1) 
 Luteinizing hormone (U/L)
3.9 (1.9)
3.6 (1.5)
3.0 (0.7)
3.7 (1.1)
3.7 (1.5) 
 Follicle-stimulating hormone (U/L)
4.0 (3.4)
3.1 (2.1)
4.1 (2.0)
4.1 (2.2)
3.8 (2.7) 
 prostate-specifi c antigen (ng/mL)
0.8 (0.5)
1.3 (1.6)
0.7 (0.2)
0.8 (0.5)
0.9 (0.9) 
 Lean body mass (kg)
60.6 (9.1)
58.9 (7.6)
60.6 (8.7)
63.9 (4.7)
60.7 (8.1) 
 Fat mass (kg)
16.4 (7.5)
13.3 (7.5)
15.7 (5.5)
17.2 (6.5)
15.7 (7.0) 
 Leg press strength (N)
1440.6 (381.0)
1364.8 (298.8)
1535.0 (287.1)
1476.1 (247.6)
1441.3 (326.8) 
 Stair-climbing power (W)
659.3 (123.1)
614.2 (125.3)
678.7 (98.4)
665.9 (136.8)
651.8 (122.2) 
 Notes : The subjects assigned to the placebo group in each of the three cohorts were pooled for the purpose of analyses. Data are mean   ( SD ). The number of 
subjects in each group is shown in row 2. FT= free testosterone; TESTO = testosterone. 
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THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 
91
5
 Plasma Lipids 
 Total and low density lipoprotein (LDL)  cholesterol did 
not change signifi cantly from baseline at any dose ( Table 2 ). 
HDL cholesterol decreased from baseline at doses   0.3 mg; 
HDL cholesterol returned to baseline after treatment discon-
tinuation ( Table 2 ). Triglyceride levels decreased from 
baseline across all doses. 
 Body Composition 
 LBM increased dose  dependently ( p for trend = .04 ; 
 Figure 3A ). The increase in LBM averaged 1.21 kg at the 
1.0 - mg dose ( p  =  .047 vs placebo). The increase in LBM 
was correlated with the dose. Fat mass ( Figure 3B ) did not 
change signifi cantly. The increase in appendicular skeletal 
muscle mass in the 0.3 - and 1.0 - mg groups was not signifi -
cantly differently from that in the placebo group (change 
from baseline   0.2, 0.04, 0.47 , and 0.37 kg for the placebo, 
0.1, 0.3, and 1.0-mg groups,  p for trend  =  .078). 
 
L4033-2: Day 1 PK
0.1
1
10
100
0
10
20
30
40
50
Time (h)
Plasma Conc. (ng/mL)Cohort 1- 0.1 mg (n=6)
Cohort 2- 0.3 mg (n=11)
Cohort 3- 1 mg (n=14)
L4033-2: Day 21 PK
0.1
1
10
100
0
30
60
90
120
150
180
Time (h)
Plasma Conc. (ng/mL)Cohort 1- 0.1 mg (n=5)
Cohort 2- 0.3 mg (n=10)
Cohort 3- 1 mg (n=11)
 
 Figure 1 .  Pharmacokinetics of  LGD-4033 in Healthy Men. Legend.LGD-4033 
concentrations were measured in venous blood collected at 0, 0.5, 1, 2, 3, 4, 6, 
8, 10, 12, 24, 28, 32, and 48  hours after the fi rst dose (upper panel). Once-daily 
dosing recommenced on day 3. On day 21, venous blood was collected at 0, 0.5, 
1, 2, 3, 4, 6, 8, 10, 12, 24, 28, 32, 48, 72, 96, 120, and 168  hours after day 21 
dosing (lower panel). 
 Muscle Performance and Physical Function 
 The increase in strength averaged 68.3 N at the 1.0-mg 
dose, but this change was not signifi cantly different from 
that in the placebo group ( Figure 3C ). Stair - climbing  speed 
and power revealed a trend toward dose-related improvement, 
but these changes did not achieve statistical signifi cance. 
 Fractional Mixed - Muscle Protein Synthesis Rates 
 Plasma phenylalanine concentrations did not change sig-
nifi cantly from 180 to 360  min utes indicating achievement 
of a steady state. Baseline FSR averaged  ~ 6% / h , consistent 
with published literature. The change in FSR from baseline, 
measured in the fasted state, did not differ signifi cantly 
between 0.3-mg dose and the placebo groups (0.033    0.016 
vs 0.031    0.011,  p  =  .99 ;  Supplementary  Appendix Table 2 ). 
 D iscussion 
 LGD-4033 was safe and well tolerated over the range of 
doses that were evaluated over a 3-week period. Even dur-
ing this short treatment period, there was clear evidence of 
the compound ' s androgenic activity, as refl ected in the 
increase in LBM, and signifi cant suppression of testosterone, 
 sex hormone  binding globulin , and HDL  cholesterol levels. 
In spite of demonstrable androgenic activity, serum  prostate-
specifi c antigen did not change signifi cantly. The study also 
revealed other attractive  PK  attributes of the drug  including 
a prolonged circulating half-life, dose - proportional systemic 
exposure, and robust relationships between the dose and 
outcomes. The gains in LBM were similar to those reported 
with another SARM ( 17 ), although the treatment duration 
in the latter trial was substantially longer (12  weeks). 
 The study had many features of a good trial design; sub-
ject allocation by randomization, concealed randomization, 
blinding, and independent appraisal of safety data by a  Data 
and Safety Monitoring Board . By virtue of being an ascending-
dose study, the study also had some inherent constraints. 
The doses of study medication were administered sequen-
tially in ascending order rather than in random order. The 
sample size, although substantially larger than in most 
phase I ascending - dose studies, was not based on consider-
ations of effect sizes, as the study ' s primary aim was to 
establish safety and tolerability rather than effi cacy. Similarly, 
the  3 -week study duration was not designed to demonstrate 
maximal effects on skeletal muscle mass and muscle strength 
which were not the primary outcomes of the trial. In light of 
these inherent constraints, it is particularly remarkable that 
signifi cant dose-dependent gains in LBM were evident in 
this short duration, indicating this SARM ' s substantial 
androgenic  anabolic activity on the skeletal muscle. 
 Several attractive  PK  features of this SARM are notewor-
thy. Its prolonged elimination half - life renders it amenable 
to once daily or even a less frequent dosing regimen. 
Daily administration of the drug was associated with dose-
proportional increase in systemic exposure resulting in 
Plasma Conc. (ng/mL)Plasma Conc. (ng/mL)Plasma Conc. (ng/mL)Cohort 1- 
 
 (n=6)
Cohort 2- 
 
 (n=11)
rt 3- 1 mg (n=14)
Plasma Conc. (ng/mL)Cohort 1- 
 
 (n=5)
rt 2- 0.3 mg (n=10)
rt 3- 1 mg (n=1)
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BASARIA ET AL.
6
 
A
B
C
D
E
F
 
 Figure 2.  (A) The effects of LGD-4033  selective androgen receptor modulator on serum total testosterone levels. Change from baseline in serum total testosterone 
levels are shown. The data are mean    standard error of the mean ( SEM ) ,  n  =  33 in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in 
the 1.0 - mg group. BL =  baseline. The shaded area highlights the 21-day treatment period.  ( B ) Change in  the  free testosterone levels from baseline. Change from 
baseline in serum free testosterone levels is shown. The data are mean   SEM,  n  =  33 in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and 
14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period.  ( C ) Change in  sex hormone  binding globulin levels from baseline. 
Change from baseline in serum  sex hormone  binding globulin levels is shown. The data are mean   SEM,  n  =  33 in the placebo group, 18 in the 0.1 - mg dose, 
11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 21-day treatment period.  ( D ) Change in luteinizing hormone 
(U/L) levels from baseline. Change from baseline in serum  luteinizing hormone levels is shown. The data are mean   SEM,  n  =  33 in the placebo group, 18 in the 
0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL =  baseline. The shaded area highlights the 21-day treatment period.  ( E ) Change in follicle -
 stimulating hormone (U/L) levels from baseline. Change from baseline in serum  follicle-stimulating hormone levels is shown. The data are mean   SEM,  n  =  33 
in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL  = baseline. The shaded area highlights the 21-day treatment 
period.  ( F ) Change in prostate - specifi c antigen (ng/mL) levels from baseline. Change from baseline in  prostate-specifi c antigen levels is shown. The data are mean   
SEM,  n  =  33 in the placebo group, 18 in the 0.1 - mg dose, 11 in the 0.3 - mg group, and 14 in the 1.0 - mg group. BL = baseline. The shaded area highlights the 
21-day treatment period. 
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THE EFFECTS OF LGD-4033, A NONSTEROIDAL SARM, IN HEALTHY MEN 
93
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predictable accumulation upon multiple dosing. There was 
a robust relationship between the dose and the plasma con-
centrations. The mean area-under-the-curves (AUC)  in men 
receiving the 0.3 - and 1.0 - mg dose were above the drug 
AUC estimated to be effi cacious in monkeys, and all three 
doses produced AUCs that exceeded the AUC estimated to 
be effi cacious in orchidectomized rats. 
 In a manner typical of all oral androgens ( 25 , 26 , 27 ), the 
oral administration of LGD-4033 was associated with sig-
nifi cant suppression of HDL  cholesterol at the 1.0-mg dose. 
Triglyceride levels also decreased, but LDL cholesterol did 
not change. Neither the mechanism nor the clinical signifi -
cance of the HDL suppression with orally administered 
androgens is well understood ( 25 ). HDL  cholesterol has 
been negatively associated with the risk of coronary artery 
disease in epidemiological studies ( 25 , 28 ); however, phar-
macologically  induced changes in HDL  cholesterol have 
not been necessarily associated with changes in cardio-
vascular risk. In animal models, the degree of anti-atherogenic 
effect of HDL  cholesterol is determined more by the mech-
anism of HDL modifi cation than by the changes in HDL 
levels ( 28 , 29 ). Thus, the increases in HDL  cholesterol due 
to overproduction of apoA1, but not due to inhibition of 
HDL catabolism, have been found to be atheroprotective 
( 28 , 29 , 30 , 31 , 32 ). The HDL lowering effect of oral androgens 
has been attributed to the upregulation of scavenger receptor 
B1 and the hepatic lipase, both of which are involved in HDL 
catabolism ( 32 , 33 ). Neither the hyperexpression of  scavenger 
receptor B1 nor that of hepatic lipase has been associated 
with acceleration of atherogenesis, even though increased 
 Table 2.  The Effects of LGD-4033  Selective Androgen Receptor 
Modulator on Plasma Lipids 
 Treatment Group * 
Mean ( SD ) 
Baseline
Mean ( SE ) Change From 
Baseline 
 Day 21
Day 56 
 Total cholesterol (mg/dL) 
 
 Placebo
163.4 (28.1)
  1.6 (2.9)
5.2 (4.2) 
 
 0.1 mg
163.3 (33.5)
  10.8 (3.6)
0.4 (5.5) 
 
 0.3 mg
168.6 (16.6)
  18.0 (4.8)
6.4 (5.0) 
 
 1 mg
175.1 (33.5)
  14.3 (8.1)
0.3 (4.4) 
 HDL cholesterol (mg/dL) 
 
 Placebo
52.5 (11.8)
  1.7 (1.2)
0.4 (1.8) 
 
 0.1 mg
56.1 (17.3)
  1.0 (2.6)
3.5 (2.3) 
 
 0.3 mg
50.3 (8.0)
  10.4 (1.4)
0.6 (1.7) 
 
 1 mg
49.2 (11.7)
  19.4 (2.1)
  1.1 (3.2) 
 LDL cholesterol (mg/dL) 
 
 Placebo
92.4 (26.2)
0.9 (2.6)
4.4 (3.7) 
 
 0.1 mg
91.0 (29.6)
  5.5 (3.3)
  4.5 (4.9) 
 
 0.3 mg
101.5 (15.9)
  2.8 (4.5)
1.7 (3.7) 
 
 1 mg
106.8 (31.6)
7.1 (7.1)
4.42 (4.0) 
 Triglycerides (mg/dL) 
 
 Placebo
92.6 (36.8)
  4.3 (4.7)
1.9 (7.5) 
 
 0.1 mg
80.0 (31.0 )
  21.4 (8.1)
7.2 (9.1) 
 
 0.3 mg
84.4 (26.1)
  24.0 (4.3)
20.8 (8.0) 
 
 1 mg
95.4 (39.1)
  10.1 (6.7)
  15.6 (8.0) 
 Notes :  * Number of subjects with at least one post - baseline test: placebo  = 
 30, 0.1 mg  =  17, 0.3 mg  =  10 , and 1 mg  =  14. LDL = Low density lipoprotein. 
 
Total Body
PBO
0.1 mg
0.3 mg
1 mg
-0.5
0.0
0.5
1.0
1.5
2.0
*
*p =0.047 vs. Placebo
A
Total Body
PBO
0.1 mg
0.3 mg
1 mg
-1.0
-0.5
0.0
0.5
1.0
B
C
PBO
0.1 mg
0.3 mg
1 mg
-50
0
50
100
150
Change from Baseline (kg)Change from Baseline (kg)Change from Baseline (Newton) 
 Figure 3.  (A) Mean ( SE ) lean mass (kg) change from baseline up to day 28. 
Change from baseline in  lean body mass is shown. The data are mean    standard 
error of the mean ,  n  =  30 in the placebo group pooled from the three cohorts, 
17 in the 0.1 - mg dose, 10 in the 0.3 - mg group, and 11 in the 1.0 - mg group. BL = 
baseline. * p  <  .05 vs placebo. PBO = placebo;  p for trend = .04.  ( B ) Mean ( SE ) 
fat mass (kg) change from baseline up to day 28. Change from baseline in fat 
mass is shown. The data are mean    standard error of the mean ,  n  =  30 in the 
placebo group pooled from the three cohorts, 17 in the 0.1 - mg dose, 10 in the 
0.3 - mg group, and 11 in the 1.0 - mg group. PBO = placebo.  p for trend = .261. 
 ( C ) Change in leg press strength (Newton) from baseline. Change from baseline 
in fat mass is shown. The data are mean    standard error of the mean ,  n  =  30 in 
the placebo group pooled from the three cohorts, 17 in the 0.1 - mg dose, 10 in the 
0.3 - mg group, and 11 in the 1.0 - mg group. PBO = placebo;  p for trend = .203. 
expression of each is associated with reduced HDL  cholesterol 
( 28 , 29 , 30 , 31 ). Thus, clinical signifi cance of the HDL decrease 
associated with oral androgens remains unclear. Long - term 
studies are needed to clarify the effects of long-term SARM 
administration on cardiovascular risk. In the interim, the 
initial trials are likely to be conducted for acute or subacute 
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BASARIA ET AL.
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indications, such as cancer cachexia and functional limita-
tions associated with acute illness or hip fracture, where 
the short-term changes in HDL  cholesterol may not be 
clinically important. 
 Exogenous androgens would be expected to lower 
endogenous testosterone levels. However, LGD-4033 has 
been shown to increase bone mineral density, periosteal 
bone formation, and femur bending strength in preclinical 
models. Other SARMs have also been shown to maintain 
measures of sexual function in the orchiectomized rodent 
model ( 18 ). 
 The mechanisms by which androgens increase muscle 
mass remain incompletely understood. Testosterone admin-
istration induces hypertrophy of both type I and type II 
muscle fi bers ( 34 ). Muscle fi ber hypertrophy can result 
from either increased muscle protein synthesis or decreased 
muscle protein degradation. Our studies did not reveal a sig-
nifi cant difference in fractional muscle protein synthesis 
between the placebo and  the  active drug groups at the 0.3-mg 
dose. These studies were conducted in the fasted state when 
the fractional muscle protein synthesis is low; however, tes-
tosterone trials that have reported an increase in FSR have 
also been conducted in the fasted state as have trials that 
failed to show improvements in FSR ( 35 ). Previous human 
and animal studies have shown inhibition of muscle prote-
olysis and muscle protein degradation pathways during 
testosterone administration, as potential mechanisms for 
increased muscle mass ( 36 , 37 ). Testosterone also increases 
the number of satellite cells ( 38 ) by promoting the prolifera-
tion of satellite cells and the differentiation of muscle progen-
itor cells ( 39 , 40 ). Those mechanisms were not investigated 
in this study. 
 The past decade has witnessed the emergence of a num-
ber of nonsteroidal SARMs from several pharmaceutical 
companies. Currently, SARMs are being developed as a 
new class of function - promoting anabolic therapies to treat 
the loss of muscle mass and function associated with aging 
and illness, cancer cachexia, osteoporosis, and other condi-
tions associated with muscle loss. This 3-week phase I study, 
by demonstrating the safety and tolerability of LGD-4033 
and signifi cant gains in muscle mass and strength, paves 
the way for longer  term effi cacy trials in one or more 
populations of older individuals for which SARMs may 
be indicated. Short-term indications for grievous condi-
tions, such as cancer cachexia or functional limitations 
following an acute illness or hip fracture, might provide 
a more attractive risk:benefi t profi le for initial trials of 
SARMs than long-term indications such as aging-associated 
sarcopenia. 
 F unding 
 This trial was supported by Ligand Pharmaceuticals. 
 S upplementary M aterial 
 Supplementary  material can be found at:  http://biomedgerontology.
oxfordjournals.org/ 
 Acknowledgment 
 The authors  thank the Data and Safety Monitoring Board: Glenn 
Cunningham, MD, and Ronal S. Swerdloff, MD. 
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